Age-associated changes in immune function in old age are a known risk factor for tuberculosis (TB) however, the contribution of the heightened systemic inflammatory state (inflammaging) often observed in elderly individuals has not been previously considered. In Aim 1 we hypothesize that inflammation in the periphery will serve as a predictive biomarker of pulmonary inflammation and susceptibility to M.tb infection in old age. We will test this hypothesis by studying the function of circulating monocytes and soluble mediators from adult and elderly donors and compare those signatures to data obtained in Projects 1 and 2 where M.tb interactions with alveolar macrophages and alveolar lining fluid are studied in the same subjects. Our goal is to identify predictive cellular and/or molecular patterns in the periphery in old age that will correlate with an increased susceptibility to M.tb infection in the lung in old age. These comparative analyses of peripheral and pulmonary immune responses extend our studies from observational to mechanistic and allow us to identify peripheral predictive biomarkers of M.tb susceptibility that may have clinical application. We also hypothesize that M.tb infection further fuels the systemic inflammaging state in old age and predisposes elderly individuals to develop symptoms of TB that are associated with increased morbidity and mortality. We will test this by investigating the inflammatory phenotype and function of peripheral blood monocytes and inflammatory and immuno- regulatory cytokines from adult and elderly subjects with latent or active TB. While inflammaging has been established as a critical factor of health-span in the elderly, adaptive immune function is essential for the control of many infectious diseases, including TB. It is unknown whether T cells can maintain their effector function throughout a long-term latent M.tb infection. We hypothesize that individuals with latent M.tb infection accumulate exhausted antigen specific T cells that no longer respond optimally to M.tb infection. We will determine the phenotype and function of M.tb specific T cells in adult and elderly subjects with latent M.tb infection and active TB, which will synergize with studies of M.tb infected mice performed in Project 3. The ability to generate a robust recall response will be determined in vitro in response to M.tb antigens and in vivo using an antigen challenge model where infiltrating lymphocytes are isolated from human TST induration biopsies. This will be the first study to determine M.tb specific adaptive immune function in elderly individuals with latent M.tb infection. Given the paucity of information regarding immune function in elderly TB patients as well as elderly with latent M.tb infection, this project is highly significant. Project 4 provides an opportunity to perform translational science within the continuum of this Program Project, and combines the proven collaborative expertise of a clinical scientist (Wang) and basic researcher (Turner).